PROJECT SUMMARY/ABSTRACT The overarching goal of this Mentored Research Scientist Development Award K01 application is to provide Dr. Verplaetse with the requisite skills and protected time to become an independent translational and clinical investigator in the field of addiction neuroscience. Dr. Verplaetse's research will focus on the behavioral and neurochemical mechanisms underlying stress-precipitated drinking behaviors in individuals with alcohol use disorders versus social drinkers. With this K01, Dr. Verplaetse's training will assist her in developing and designing innovative research in the field of alcohol addiction by gaining a better understanding of: (1) PET imaging techniques to examine neurochemical mechanisms underlying stress-precipitated drinking behavior; (2) techniques for stress induction to assess the ability to resist drinking and stress-precipitated alcohol consumption in the human laboratory; (3) translational mechanisms by which neuroscience is integrated with human laboratory investigations to facilitate novel research ideas and hypotheses related to alcohol and stress system reactivity; and {{{(4) sex differences in stress-related drinking and associated mechanisms}}}. The opportunities afforded by the K01 mechanism would enable the candidate to embark on a rigorous, structured 5-year program of mentorship, training, and research, designed to provide her with the necessary skills in the areas highlighted above and to become an independent research scientist. This program of study will combine formal didactic training (e.g., courses on Ethical and Practical Issues in Clinical Investigation and Neuroimaging in Neuropsychiatry), attendance to scientific research conferences, structured meetings with mentors and collaborators, and one-on-one mentored research training. In pursuit of this goal, the candidate proposes to undertake further training in three primary areas: (1) positron emission tomography (PET) imaging using a novel radiotracer to measure HPA axis reactivity in the living human brain; (2) human laboratory modeling of stress-precipitated drinking behavior; and (3) advanced statistical training for the evaluation and integration of PET imaging data and stress-precipitated drinking data. The research component, which is synergistic with the training program, is focused on the elucidation of neurochemical mechanisms underlying stress-precipitated alcohol-motivated behaviors and the role of the HPA axis and glucocorticoid systems in individuals with alcohol use disorders. Dr. Verplaetse's long-term research goal is to use a combined PET and human laboratory paradigm to further understand the mechanisms underlying stress-induced alcohol-seeking and consumption to identify novel treatment targets for alcohol use disorders, with an emphasis on gender- sensitive treatment development. This interfaces with her long-term training goal of developing translational research skills that will better enable her to independently lead an innovative and multidisciplinary research program on stress-precipitated drinking behaviors and interventions targeting the brain stress systems.